Fertility and Pregnancy-Associated ß-Cell Proliferation in Mice Deficient in Proglucagon-Derived Peptides

Abstract

Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ß-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcggfp/gfp), which lack all the peptides derived from proglucagon. Female Gcggfp/gfp mice could deliver and raise Gcggfp/gfp pups to weaning and Gcggfp/gfp pups from Gcggfp/gfp dams were viable and fertile. Pregnancy induced ß-cell proliferation in Gcggfp/gfp mice as well as in control mice. However, serum insulin levels in pregnant Gcggfp/gfp females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcggfp/gfp females were higher after gestational day 12. Gcggfp/gfp females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcggfp/gfp females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated ß-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcggfp/gfp mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods.

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

“…Interestingly, phospho-mTOR/mTOR was upregulated, consistent with the hypertrophic phenotype of late gestation (Figure 3A and ONLINE FIGURE IIA). Circulating insulin levels, as reported previously 18, 19 , were elevated in late pregnancy (Online Figure IID). …”

Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

“…In contrast, the involvement of gut hormones which normally play a key role in the regulation of beta cell function and survival has been largely overlooked. Interestingly, Sugiyama et al observed that beta cell proliferation was not affected in pregnant glucagon-GFP knock-in (Gcg gfp /Gcg gfp ) mice lacking global proglucagon derived peptides, including glucagon, GLP-1, GLP-2 and oxyntomodulin [48] . However, recent studies have shown that these mice display important compensatory changes even in the non-pregnant state, including markedly increased circulating GIP with substantial ectopic expression of GIP in islet beta cells [29] .…”

Alterations of Glucose-Dependent Insulinotropic Polypeptide and Expression of Genes Involved in Mammary Gland and Adipose Tissue Lipid Metabolism during Pregnancy and Lactation

“…Factors responsible for this are poorly understood but have been suggested to include prolactin, placental lactogens, progesterone and oestrogen [19] . Interestingly, it has recently been shown that proglucagon-derived peptides, such as glucagon-like peptide-1 (GLP-1), are not required for pregnancy-associated beta-cell proliferation [28] . Thus, the present evidence that most alpha-cells co-expressed GIP as well as glucagon is potentially interesting given well established effects of GIP on beta-cell proliferation and survival [20] , [21] .…”